The compound omeprazole of formula (I) and chemical name (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole), and therapeutically acceptable salts thereof, is well known as an effective gastric acid secretion inhibitor and is useful as an anti-ulcer agent as was first described in EP 0005129.

The sulphur atom of the sulfoxide group in asymmetrically substituted sulfoxides, as in omeprazole, is chiral. Therefore, omeprazole has two enantiomeric forms, the (R) and (S)-enantiomers, otherwise known as (R)-omeprazole and (S)-omeprazole, and normally exists as a racemic mixture. (S)-Omeprazole, with structural formula (II), is referred to as esomeprazole.

Certain methods for the preparation or separation of the enantiomers of omeprazole are known in the art. For example, DE 4035455 relates to a resolution process of omeprazole via formation of diastereomeric 1-substituted benzimidazole derivatives which are separated and thereafter hydrolysed in acidic solution. The enantiomers of omeprazole are unstable to the acidic conditions required for hydrolysis of the attached group and the acid has to be rapidly neutralised with a base to avoid excessive degradation. Moreover, the enantiomers of omeprazole are unstable to temperatures in excess of 50-60° C. The exothermicity of rapid neutralisation will lead to further degradation and is difficult to handle in large scale production.
WO 94/27988 discloses a reaction between a 6-methoxy-1-chloromethyl analogue of omeprazole and (R)-mandelic acid sodium salt in chloroform, resulting in a diastereomeric mixture which may be separated by reverse phase chromatography and subsequently hydrolysed to afford both enantiomers of omeprazole.
WO 96/02535 discloses a process for the preparation of the single enantiomers of omeprazole by asymmetric oxidation of the corresponding prochiral sulphide. The process employs an oxidizing agent and a chiral titanium complex which may include a titanium (IV) compound.
(S)-Omeprazole in a neutral, solid form (which can be in a partly or substantially crystalline state) is first described in WO 98/28294.
WO 02/098423 relates to an inclusion complex of (S)-omeprazole with cyclodextrins. The process comprises adding a cyclodextrin to an aqueous solution of a substantially pure optical isomer of a benzimidazole compound or a pharmaceutically acceptable salt thereof, and isolating the inclusion complex so formed from the solution.
CN 1223262 relates to a process for the preparation of optically pure anti-peptic ulcer benzimidazole drugs, including esomeprazole. The method makes use of bi-2-naphtol, bi-2-phenanthrol, or tartaric acid derivatives as inclusion complexation hosts for the resolution of racemic omeprazole. The method comprises dissolving racemic omeprazole and the inclusion host [preferably 2,2′-dihydroxy-1,1′-binaphthyl (BINOL)] in a benzene/hexane mixture. The enantiomeric excess (e.e.) of the inclusion complex obtained can be increased by consecutive recrystallisations. The inclusion complex is separated on a SiO2 column to give (S)-omeprazole.
Despite the teaching of this prior art, there still remains a need for a new process for the preparation of substantially optically pure (S)-isomer of omeprazole and its pharmaceutically acceptable salts and solvates, including hydrates.